Targeting RNA metabolism to sensitize pancreatic ductal adenocarcinoma to therapeutic treatments

Co-treatment with gemcitabine and nab-paclitaxel exerts additive effects on pancreatic cancer cell death: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer and current treatments exert small effects on life expectancy. The most common adjuvant treatment for PDAC is gemcitabine. However, relapse almost invariably occurs and most patients develop metastatic, incurable disease. The aim of the present study was to assess the activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) alone or in combination with gemcitabine in PDAC cell lines displaying different degrees of sensitivity to gemcitabine treatment. We evaluated the effects of gemcitabine and nab-paclitaxel and their combination on cell proliferation, death, apoptosis and cell cycle distribution in PDAC cell lines either sensitive to gemcitabine, or with primary or secondary resistance to gemcitabine. Our results indicated that the dose‑response of PDAC cell lines to nab-paclitaxel was similar, regardless of their sensitivity to gemcitabine. In addition, nab-paclitaxel elicited similar cytotoxic effects on a PDAC cell line highly resistant to gemcitabine that was selected after prolonged exposure to the drug. Notably, we found that combined treatment with gemcitabine and nab-paclitaxel exerted additive effects on cell death, even at lower doses of the drugs. The combined treatment caused an increase in cell death by apoptosis and in cell cycle blockage in S phase, as assessed by flow cytometry and western blot analysis of the PARP-1 cleavage. These results revealed that a combined treatment with nab-paclitaxel may overcome resistance to gemcitabine and may represent a valuable therapeutic approach for PDAC